Method for treating or preventing dry eye disorders using alkylamino-polyhydroxyalkanes

ABSTRACT

Method for the treatment or prophylaxis of dry eye disorders by the administration of alkylamino-polyhydroxyalkanes and compositions thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional PatentApplication No. 61/043,162, filed Apr. 8, 2008, the entire disclosure ofwhich is incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to the use of certainalkylamino-polyhydroxyalkanes for the treatment or prevention of dry eyedisorders.

BACKGROUND OF THE INVENTION

The eye surface is kept moist by a tear film composed of an oily layer,a watery layer and a layer of mucus. The outermost oily layer isproduced by the meibomian glands and reduces tear evaporation. Themiddle layer is the watery liquid typical of tears and is produced bylacrimal glands. The inner layer of mucus is produced by goblet cells inthe conjunctiva, and enables the watery layer to evenly coat the eye.Mucins are the main component of mucus and have an important role inmaintaining the aqueous and oily layers of the eye film.

Dry eye (keratoconjunctivitis sicca or keratitis sicca) is a chronicdryness of the corneal and conjunctival surfaces and results from adecrease in the production of tear components or from an altered ratioof the individual oil, water and mucus components to each other. Peoplewith dry eye have various symptoms including redness, soreness, burning,itching, photophobia, blurred vision, foreign body sensation(grittiness) and contact lens intolerance. Environmental conditions canworsen these symptoms.

Dry eye can be a side effect caused by certain drugs such as diuretics,beta blockers, antihistamines, sleeping pills, or pain relievers. TheLASIK (laser assisted in situ keratomileusis) procedure can cause dryeye due to corneal denervation (Toda, 2007). Several hormones impacttear component production and hormone insufficiency can cause dry eye(Sullivan, 2004). The prevalence of dry eye increases with age and ishigher among women (Moss et al. 2000).

Dry eye can be classified as either tear production deficient orevaporative dry eye (Lemp, 1995). The former includes Sjogren-associatedand non-Sjogren associated dry eye. Sjogren's disease is an autoimmunesyndrome of the exocrine glands that includes dry eyes and dry mouth(Srinvassan and Siomovic, 2007). In both of these conditions, there isan inflammatory environment characterized by T cell infiltration of theconjunctiva, and increased levels of the inflammatory cytokines tumornecrosis factor (TNF), interleukin 1 alpha (IL-1a), IL-6, IL-8 and IL-10(Zoukhri, 2006). These factors result in alterations of the conjunctivalepithelia, a loss of goblet cells and a decrease in mucin production.

Current therapies for dry eye include the use of artificial tears torehydrate the ocular surface and provide symptomatic relief. Theirbenefits are short lived, however, and frequent dosing is required.Other therapies include steroids (U.S. Pat. No. 5,958,912), cyclosporineA (Tauber, 1998), hydroxyeicosatetraenoic acid derivatives (U.S. Pat.No. 5,696,166), adenine analogues (Jumblatt and Jumblatt, 1998),purinergic receptor antagonists (U.S. Pat. No. 5,900,407),phosphodiesterase inhibitors (U.S. Pat. No. 4,753,945), glycosides (U.S.Pat. No. 7,223,737), melanocyte stimulating hormones (U.S. Pat. No.4,868,154), and conjugated estrogens (U.S. Pat. No. 5,041,434).

Goblet cells are the primary source of excreted mucin. The cornea andconjunctival epithelial cells also produce transmembrane mucin tomaintain a hydrated surface. Lacrimal cells produce a small solublemucin. Dry eye causes changes in both the secreted andmembrane-associated mucins (Gipson et al. 2004). Release of mucin fromconjunctival cells is regulated by neurotransmitters.

There is an interest in treating dry eye with agents that can increasemucin production. Nicotinic receptor agonists have been reported tostimulate conjunctival cells to secrete mucin (U.S. Pat. No. 6,277,855).The purinoreceptor P2Y₂ agonist INS365 increased goblet cell density ina rat model of dry eye (Fujihara et al., 2001). Some anti-ulcer drugsstimulate mucus secretion. The anti-ulcer drug gefarnate increasesconjunctival goblet cell density in a rabbit model of dry eye (Nakamuraet al. 1998). Hormone replacement therapy for post-menopausal womencauses an increase in conjunctival goblet cell density (Pelit et al.2003). Cyclosporine treatment results in an increase in goblet cellnumbers in patients with dry eye (Kunert et al. 2002).

As goblet cells are present in other tissues (digestive and respiratoryepithelia; agents that increase mucin production may have additionalutilities in treating conditions such as constipation, anorexia, drymouth (xerostomia) and respiratory pathologies (Shimotoyodome et al.,2000; Deplancke and Gaskins, 2001).

SUMMARY OF THE INVENTION

In accordance with one embodiment, the present invention provides amethod of treating or preventing dry mucus membrane disorders that canbe alleviated by increasing mucin production, e.g., dry eyes, dry mouthand age-related constipation in a patient in need thereof byadministering to the patient a therapeutically or prophylacticallyeffective amount of a compound having the formula:

wherein R represents a substituted or unsubstituted alkyl (C₁-C₄), saidalkyl substituents being selected from the group of hydroxy, carboxy,and phosphono substituents;

R₁ and R₂ are the same or different and represent a radical selectedfrom the group consisting of hydrogen and hydroxymethyl radicals;

R₃ and R₄ are the same or different and represent a hydrogen or hydroxyradical;

R₅ and R₆ are different and represent either a hydrogen or hydroxyradical;

R₇ and R₈ are different and represent either a hydrogen or hydroxyradical;

R₉, R₁₀ and R₁₁ are the same or different and represent a radicalselected from the group consisting of hydrogen, alkyl (C₁-C₂),hydroxyalkyl and hydroxy radicals;

n represents either 0 or 1;

the pharmaceutical acceptable salts and isomeric forms of said compound.

In another embodiment, this invention provides a method of forprophylaxis of dry eye disorders in a patient in need of thereof, themethod comprising administering to the patient a prophylacticallyeffective amount of a compound of formula I, above.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows examples of goblet cell densities for eye tissues fromscopolamine dosed animals treated with either a saline eyemist (panels Aand B) or oral meglumine (panels C and D). The animals on oral meglumine(panels) have more extensive regions containing goblet cells.

DETAILED DESCRIPTION OF THE INVENTION

Although the method of the present invention is applicable to a range ofdry mucus membrane disorders, it will be described hereinbelow withparticular emphasis on the treatment of dry eyes.

A representative example of the synthesis of hydrochloride salts of theabove alkylamino-polyhydroxyalkanes is as follows:

An aldose or ketose sugar (2 mmol) is dissolved in 10 ml of methanol andan appropriate amine (1.5 mmol) in methanol is added followed by 1 ml ofa slurry of activated Raney nickel. This is shaken under 28 psi ofhydrogen for 18 hours. The catalyst is removed by filtration and thefiltrate evaporated. The residue is dissolved in 2 ml of water andpurified by ion-exchange chromatography on a Dowex-50 column (1×10 cm).The column is washed with water to remove excess sugar and the producteluted with a linear gradient of 0 to 10% ammonium hydroxide (50 ml).Evaporation of the ammonia yields the free base which is converted toits hydrochloride salt by neutralizing with 1N HCL. Evaporation of thesolvent yields the hydrochloride salt of thealkylamino-polyhydroxyalkane.

The compounds represented by formula I, above, are intended to includeall possible isomeric forms thereof including structural isomers andstereoisomers or conformational isomers.

The compounds described herein can form pharmaceutically acceptablesalts with various inorganic or organic acids or bases. Suitable basesinclude, e.g., alkali metal salts, alkaline earth metal salts, ammonium,substituted ammonium and other amine salts. Suitable acids include,e.g., hydrochloric acid, hydrobromic acid and methanesulfonic acid.

The pharmaceutically acceptable salts of the compounds of formula I canbe prepared following procedures which are familiar to those skilled inthe art.

The above-described compounds and their pharmaceutically acceptablesalts can be used to prepare pharmaceutical compositions which alsocomprise a pharmaceutically acceptable carrier medium or auxiliaryagent.

The pharmaceutical composition may be prepared in various forms foradministration, including both liquids and solids. Thus, the compositionmay be in the form of tablets, caplets, pills or dragees, or can befilled in suitable containers, such as capsules, or, in the case ofsolutions or suspensions, filled into bottles. As used herein,“pharmaceutically acceptable carrier medium” includes any and allsolvents, diluents, buffers or other liquid vehicle, dispersion orsuspension aids, surface active agents, tonicity agents, viscositymodifiers, e.g., thickening or emulsifying agents, preservatives,antimicrobial agents, solid binders, lubricants, dissolution aids andthe like, as suited to the particular dosage form desired.Representative examples of suitable carrier media include gelatine,lactose, starch, magnesium stearate, talc, vegetable and animal fats andoils, gums, polyalkylene glycol, water, or the like. Remington: TheScience and Practice of Pharmacy, 20^(th) Edition, A. R. Gennaro et al.(Lippincott, Williams & Wilkins, Baltimore, Md. (2000)) disclosesvarious carriers used in formulating pharmaceutical compositions, e.g.,for topical ophthalmic and oral administration, as well as knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutical composition, its use is contemplatedto be within the scope of this invention.

In the pharmaceutical composition of the invention, the active agent(s)may be present in an amount of at least 0.0001% and generally not morethan about 10.0% by weight, based no the total weight of thecomposition, including carrier medium and/or auxiliary agent(s), if any.Preferably, the proportion of active agent varies between 0.001%-0.0l%by weight of the composition. One or more supplementary active agent mayalso be included in the pharmaceutical compositions of this invention.For example, steroids, cyclosporine A, hydroxyeicosatetraenoic acidderivatives, adenine analogues, purinergic receptor antagonists,phosphodiesterase inhibitors, glycosides, melanocyte stimulatinghormones, purinoreceptor P2Y₂ agonists, or conjugated estrogens may beused as a supplementary active agent for the purpose of preventing lossof mucin production from goblet cells.

Auxiliary agents, such as compounds that will protect the activecompound from acid destruction in the stomach or facilitate theabsorption of the active compound into the bloodstream can also beincorporated into the pharmaceutical composition, if necessary ordesirable. Other auxiliary agents commonly used in ophthalmicpreparations, such as aloe vera gel or other agents that improve oculartolerance are also beneficially included in the compositions describedherein. Absorption can also be enhanced by delivering the activecompound by means of a liposome or nanoparticle carrier.

The compounds of Formula I, above, along with any supplementary activeagent(s) may be administered using any amount and any route ofadministration effective for the treatment or prophylaxis of dry eyedisorders. Thus, the expression “therapeutically effective amount”, asused herein, refers to an amount of a compound of Formula I, above,which is both non-toxic and sufficient to relieve or eliminate dry eyesymptoms. The effective amount of a given compound and its optimal modeof administration are determined in accordance with established medicalstandards, taking into account the species, age, gender, weight andhealth of the patient, the nature and severity of the dry eye disorderbeing treated, the particular compound being administered, its route ofadministration, the judgment of the attending medical professional, andthe like. Similarly, the expression “prophylactically effective amount”,as used herein, refers to an amount of a compound or compositiondescribed herein which is sufficient to protect the recipient againstdevelopment of a dry eye disorder.

The compounds of the invention are preferably formulated in dosage unitform for ease of administration and uniformity of dosage. “Dosage unit”form as used herein refers to a physically discrete unit of one or morecompounds described herein which is appropriate for the patient to betreated. Each dosage should contain the quantity of active agentcalculated to produce the desired therapeutic or prophylactic effectwhen administered as such, or in association with the selectedpharmaceutical carrier medium. The appropriate quantity of therapeuticagent to be included in a specific dose form, so as to provide such aneffect can be determined by procedures well known in the art, and shouldbe such as to achieve an appreciable beneficial change over time in thedisorder being treated or to preclude manifestation of symptoms in thefirst instance.

The compounds of the invention may be administered topically, enterallyor parenterally, such as by subcutaneous injection, intramuscularinjection, intraperitoneal injection, intravenous infusion, transdermalpatch, or the like, depending on the nature of the condition beingtreated. Oral, topical ocular (eye drops, eye wash) are particularlypreferred, provided the dosage is capable of generating plasma and/ortarget tissue levels of the compound that are therapeutically active.Those skilled in the art can readily measure the levels of a smallmolecule therapeutic or prophylactic agent in plasma or target tissue.The concentration of the active agent in these samples can be comparedwith a predetermined effective amount established in vitro to assess itsefficacy.

The compounds of the invention will typically be administered once perday or up to 4-5 times per day, depending upon the particularcompound(s) chosen. While a dosing schedule of once-a-day is preferred,a more frequent dosing schedule may be required. However, the exactregimen for administration of the compound(s) and compositions describedherein will necessarily be dependent on the needs of the individualpatient being treated, the type of treatment administered and thejudgment of the attending physician. As used herein, the term “patient”refers to animals, including mammals, preferably humans.

The therapeutic method and prophylactic method of the invention willnormally include medical follow-up to determine or assess whether theintended effect is being brought about in the patient undergoingtreatment with the compound(s) described herein.

The following example describes the invention in further detail. Thisexample is provided for illustrative purposes only and should in no waybe construed as limiting the invention or its applicability in treatingdry eye conditions.

EXAMPLE 1

Sprague-Dawley male rats (7 weeks old, average weight=444 g) weretreated with subcutaneous (SC) scopolamine hydrobromide in normal saline(n=30, 25 mg/kg injected 3× per day) or nothing (n=4). Scopolaminetreated animals received either (a) 50 mM meglumine in the drinkingwater (n=10), (b) a 3× daily eyemist containing 2% by weight ofmeglumine hydrochloride (n=10) or (c) a 3× daily eyemist of normalsaline (n=10). Treatment was for 4.5 weeks. One animal receivingscopolamine and the meglumine eyemist died just prior to the end of thestudy, and the eye tissues were not analyzed. Animals were euthanizedand the eye orbit and surrounding tissue from both eyes were removed andplaced in formalin. Tissues were embedded in paraffin, thin sectionsprepared, and stained with periodic acid Schiff to more easily visualizethe goblet cells.

Table 1, below, shows independent, blinded ratings of the goblet celldensities. Animals not treated with scopolamine or with scopolamine anda saline eyemist had the lowest levels of goblet cells. Animals treatedwith scopolamine and oral meglumine had the highest levels of gobletcells. The difference in goblet cell density between the untreatedanimals and those treated with oral meglumine was significant for onegrader (p=0.04) and approached significance for the other (p=0.07). Themeglumine eye mist referred to in Table 1 was obtained from PiedmontChemical Industries (High Point, N.C.).

FIG. 1 shows examples of goblet cell densities for eye tissues fromanimals treated with scopolamine and either a saline eyemist (panels Aand B) or oral meglumine (panels C and D). The animals on oral meglumine(panels) have more extensive regions containing goblet cells.

TABLE 1 Goblet Cell Rating (Avg ± SD) Grader 1 Grader 2 oral meg 2.40 ±0.75 2.22 ± 0.93 meg eyemist 1.95 ± 0.83 1.91 ± 0.82 saline eyemist 1.67± 1.03 1.26 ± 0.84 control (no 1.63 ± 1.06 1.59 ± 0.97 scopolamine)t-test oral meg vs control 0.04 0.07 Grader ratings for thin sections ofrat eye tissues from animals with various treatments. Rating 1 = fewgoblet cells and rating 5 = many goblet cells.

A number of patent and non-patent publications are cited in theforegoing specification in order to describe the state of the art towhich this invention pertains. The entire disclosure of each of thesepublications is incorporated by reference herein.

While certain embodiments of the present invention have been describedand/or exemplified above, various other embodiments will be apparent tothose skilled in the art from the foregoing specification. The presentinvention is, therefore, not limited to the particular embodimentsdescribed and/or exemplified, but is capable of considerable variationand modification without departure from the scope of the appendedclaims.

REFERENCES

-   Deplancke, B. and H R Gaskins. (2001) Microbial modulation of innate    defense: goblet cells and the intestinal mucus layer. Am J Clin Nutr    73(suppl):1131S-1141S.-   Fujihara, T., T. Murakami, H. Fujita, M. Nakamura, and K.    Nakata. (2001) Improvement of corneal barrier function by the P2Y₂    agonist INS365 in a rat dry eye model. Invest Ophthalmol 42:96-100.-   Gipson, I. K., Y. Hori and P. Argueso. (2004) Character of ocular    surface mucins and their alteration in dry eye disease. Ocul Surf    2:131-148.-   Jumblatt, J. E. and M. M. Jumblatt. (1998) Regulation of ocular    mucin secretion by P2Y₂ nucleotide receptors in rabbit and human    conjunctiva. Exp Eye Res 67:341-346.-   Kunert, K., S. A. S. Tisdale, I. K. Gipson. (2002) Goblet cell    numbers and epithelial proliferation in the conjunctiva of patients    with dry eye syndrome treated with cyclosporine. Arch Ophthalmol    120:330-337.-   Lemp, M. A. (1995) Report of the National Eye Institute/Industry    workshop on clinical trials in dry eyes. CLAO J. 21(4):221-232.-   Moss, S. E., R. Klein, and B. E. K. Klein. (2000) Prevalence of and    risk factors for dry eye syndrome. Arch Ophthalmol. 118:1264-1268.-   Nakamura, M., K. Endo, K. Nakata, and T. Hamano. (1998) Gefarnate    increases PAS positive cell density in rabbit conjunctiva. Br J    Ophthalmol 82:1320-1323.-   Pelit A., T. Bagis, F. Kayaselcuk, D. Dursun, Y. Akova and P.    Aydin (2003) Tear function tests and conjunctival impression    cytology before and after hormone replacement therapy in    postmenopausal women. Eur J Ophthalmol 13:337-342.-   Shimotoyodome, A., S Megurok T Hase, I Tokimitsu and T    Sakata. (2000) Decreased colonic mucus in rats with    loperamide-induced constipation. Comp Biochem Physiol—Part A    Molecular and Integrative Physiology. 126:203-212.-   Srinivasan, S. and A. R. Siomovic. (2007) Sjogren syndrome. Compr    Ophthalmol Update 8:205-12.-   Sullivan, D. A. (2004) Tearful relationships? Sex, hormones, the    lacrimal gland, and aqueous-deficient dry eye. Ocul Surf 2:92-123.-   Tauber, J. (1998) Lacrimal Gland, Tear Film and Dry Eye    Syndromes 2. J. Adv. Exp. Med. Biol., 438: 969.-   Toda I. (2007) LASIK and dry eye. Compr Ophthalmol Update 8:79-85.-   Zoukhri, D. (2006) Effect of Inflammation on lacrimal gland    function. Exp Eye Res 82:885-898.

1. A method for treatment or prophylaxis of a dry mucus membranedisorder that can be alleviated by increasing mucin production, themethod comprising administering to a patient in need of said treatmentor prophylaxis an effective amount of a compound of the formula:

wherein R represents a substituted or unsubstituted alkyl (C₁-C₄), saidalkyl substituents being selected from the group of hydroxy, carboxy,and phosphono substituents; R₁ and R₂ are the same or different andrepresent a radical selected from the group consisting of hydrogen andhydroxymethyl radicals; R₃ and R₄ are the same or different andrepresent a hydrogen or hydroxy radical; R₅ and R₆ are different andrepresent either a hydrogen or hydroxy radical; R₇ and R₈ are differentand represent either a hydrogen or hydroxy radical; R₉, R₁₀ and R₁₁ arethe same or different and represent a radical selected from the groupconsisting of hydrogen, alkyl (C₁-C₂), hydroxyalkyl and hydroxyradicals; n represents either 0 or 1, the pharmaceutical acceptablesalts and isomeric forms of said compound.
 2. The method of claim 1,wherein said disorder is selected from the groups consisting of dryeyes, dry mouth and constipation.
 3. The method of claim 1, wherein saiddisorder is dry eyes.
 4. The method according to claim 1, wherein saidcompound is administered in the form of a composition further comprisinga pharmaceutically acceptable carrier.
 5. The method according to claim4, wherein the compound of formula I is present in said composition inan amount of at least 0.0001% to about 10.0% by weight, based on thetotal weight of the composition.
 6. The method according to claim 4,wherein the compound of formula I is present in an amount between 0.001%and 0.01%.
 7. The method according to claim 1, wherein said compound ismeglumine.
 8. The method according to claim 1, wherein said patient is amammal.
 9. The method according to claim 1 wherein said patient is ahuman.
 10. The method according to claim 1 wherein said compound isorally administered.
 11. The method according to claim 1 wherein saidcompound is topically administered.
 12. The method according to claim 3,wherein said compound is meglumine.
 13. The method according to claim 3,wherein said patient is a mammal.
 14. The method according to claim 3,wherein said patient is a human.
 15. The method according to claim 3,wherein said compound is orally administered.
 16. The method accordingto claim 3, wherein said compound is topically administered.